The New England journal of medicine · 2018
Emily E Groopman、Maddalena Marasa、Sophia Cameron-Christie 等
BACKGROUND: Exome sequencing is emerging as a first-line diagnostic method in some clinical disciplines, but its usefulness has yet to be examined for most constitutional disorders in adults, including chronic kidney disease, which affects more than 1 in 10 persons globally. METHODS: We conducted exome sequencing and diagnostic analysis in two cohorts totaling 3315 patients with chronic kidney disease. We assessed the diagnostic yield and, among the patients for whom detailed clinical data were available, the clinical implications of diagnostic and other medically relevant findings. RESULTS: In all, 3037 patients (91.6%) were over 21 years of age, and 1179 (35.6%) were of self-identified non-European ancestry. We detected diagnostic variants in 307 of the 3315 patients (9.3%), encompassing 66 different monogenic disorders. Of the disorders detected, 39 (59%) were found in only a single patient. Diagnostic variants were detected across all clinically defined categories, including congenital or cystic renal disease (127 of 531 patients [23.9%]) and nephropathy of unknown origin (48 of 281 patients [17.1%]). Of the 2187 patients assessed, 34 (1.6%) had genetic findings for medically actionable disorders that, although unrelated to their nephropathy, would also lead to subspecialty referral and inform renal management. CONCLUSIONS: Exome sequencing in a combined cohort of more than 3000 patients with chronic kidney disease yielded a genetic diagnosis in just under 10% of cases. (Funded by the National Institutes of Health and others.).
Genetics in medicine : official journal of the American College of Medical Genetics · 2025
Rajshree Pandey、Noemi Fluetsch Brennan、Kalliopi Trachana 等
PURPOSE: To systematically evaluate the diagnostic yield and clinical utility of genome sequencing (GS) and exome sequencing (ES; genome-wide sequencing [GWS]) in pediatric patients with rare and undiagnosed genetic diseases. METHODS: We conducted a meta-analysis of studies published between 2011 and 2023. To address study heterogeneity, comparative analyses included within-cohort studies using random-effects models. RESULTS: We identified 108 studies including 24,631 probands with diverse clinical indications. The pooled diagnostic yield among within-cohort studies (N = 13) for GWS was 34.2% (95% CI: 27.6-41.5; I2: 86%) vs 18.1% (95% CI: 13.1-24.6; I2: 89%) for non-GWS, with 2.4-times odds of diagnosis (95% CI: 1.40-4.04; P < .05). The pooled diagnostic yield among within-cohort studies (N = 3) for GS was 30.6% (95% CI: 18.6-45.9; I2: 79%) vs 23.2% (95% CI: 18.5-28.7; I2: 58%) for ES, with 1.7-times the odds of diagnosis (95% CI: 0.94-2.92; P = .13). In first-line testing, the diagnostic yield tended to be higher for GS than for ES across clinical subgroups. The pooled clinical utility among patients with a positive diagnosis was 58.7% (95% CI: 47.3-69.2; I2: 81%) for GS and 54.5% (95% CI: 40.7-67.6; I2: 87%) for ES. CONCLUSION: GS appears to have a higher diagnostic yield than ES, with similar clinical utility per positive diagnosis.
Current Genetic Medicine Reports · 2015
J. Picoraro、W. Chung
暂无摘要
American journal of human genetics · 2019
Dorota Monies、Mohammed Abouelhoda、Mirna Assoum 等
We report the results of clinical exome sequencing (CES) on >2,200 previously unpublished Saudi families as a first-tier test. The predominance of autosomal-recessive causes allowed us to make several key observations. We highlight 155 genes that we propose to be recessive, disease-related candidates. We report additional mutational events in 64 previously reported candidates (40 recessive), and these events support their candidacy. We report recessive forms of genes that were previously associated only with dominant disorders and that have phenotypes ranging from consistent with to conspicuously distinct from the known dominant phenotypes. We also report homozygous loss-of-function events that can inform the genetics of complex diseases. We were also able to deduce the likely causal variant in most couples who presented after the loss of one or more children, but we lack samples from those children. Although a similar pattern of mostly recessive causes was observed in the prenatal setting, the higher proportion of loss-of-function events in these cases was notable. The allelic series presented by the wealth of recessive variants greatly expanded the phenotypic expression of the respective genes. We also make important observations about dominant disorders; these observations include the pattern of de novo variants, the identification of 74 candidate dominant, disease-related genes, and the potential confirmation of 21 previously reported candidates. Finally, we describe the influence of a predominantly autosomal-recessive landscape on the clinical utility of rapid sequencing (Flash Exome). Our cohort's genotypic and phenotypic data represent a unique resource that can contribute to improved variant interpretation through data sharing.
Genetics in medicine : official journal of the American College of Medical Genetics · 2013
Robert C Green、Jonathan S Berg、Wayne W Grody 等
In clinical exome and genome sequencing, there is a potential for the recognition and reporting of incidental or secondary findings unrelated to the indication for ordering the sequencing but of medical value for patient care. The American College of Medical Genetics and Genomics (ACMG) recently published a policy statement on clinical sequencing that emphasized the importance of alerting the patient to the possibility of such results in pretest patient discussions, clinical testing, and reporting of results. The ACMG appointed a Working Group on Incidental Findings in Clinical Exome and Genome Sequencing to make recommendations about responsible management of incidental findings when patients undergo exome or genome sequencing. This Working Group conducted a year-long consensus process, including an open forum at the 2012 Annual Meeting and review by outside experts, and produced recommendations that have been approved by the ACMG Board. Specific and detailed recommendations, and the background and rationale for these recommendations, are described herein. The ACMG recommends that laboratories performing clinical sequencing seek and report mutations of the specified classes or types in the genes listed here. This evaluation and reporting should be performed for all clinical germline (constitutional) exome and genome sequencing, including the "normal" of tumor-normal subtractive analyses in all subjects, irrespective of age but excluding fetal samples. We recognize that there are insufficient data on penetrance and clinical utility to fully support these recommendations, and we encourage the creation of an ongoing process for updating these recommendations at least annually as further data are collected.
Clinical genetics · 2020
Go Hun Seo、Taeho Kim、In Hee Choi 等
EVIDENCE, an automated variant prioritization system, has been developed to facilitate whole exome sequencing analyses. This study investigated the diagnostic yield of EVIDENCE in patients with suspected genetic disorders. DNA from 330 probands (age range, 0-68 years) with suspected genetic disorders were subjected to whole exome sequencing. Candidate variants were identified by EVIDENCE and confirmed by testing family members and/or clinical reassessments. EVIDENCE reported a total 228 variants in 200 (60.6%) of the 330 probands. The average number of organs involved per patient was 4.5 ± 5.0. After clinical reassessment and/or family member testing, 167 variants were identified in 141 probands (42.7%), including 105 novel variants. These variants were confirmed as being responsible for 121 genetic disorders. A total of 103 (61.7%) of the 167 variants in 95 patients were classified as pathogenic or probably to be pathogenic before, and 161 (96.4%) variants in 137 patients (41.5%) after, clinical assessment and/or family member testing. Factor associated with a variant being regarded as causative includes similar symptom scores of a gene variant to the phenotype of the patient. This new, automated variant interpretation system facilitated the diagnosis of various genetic diseases with a 42.7% diagnostic yield.
Clinical Genetics · 2025
Alfiya Fasaludeen、M. Jose、U. Aswathi 等
Studies from the subcontinent on the utility of Whole Exome Sequencing (WES) in electro‐clinical phenotypes of childhood‐onset drug‐resistant epilepsy (DRE) syndromes, particularly the developmental and epileptic encephalopathies (DEE), are rare in the literature. Patients with DRE phenotypes of presumed genetic etiology with an age of onset of epilepsy < 12 years, with/without developmental encephalopathy, were included in this study. Our study cohort (N = 175) included 158 trios, 6 duos, and 11 proband‐only samples. Age at onset of seizures was ≤ 3 years in 76.6% and > 3 years in 23.4%, with developmental delay noted in 80.6% of the cohort. The overall yield of pathogenic/likely pathogenic variants in WES was 38.9% (68/175, 19 were novel); for trio‐WES it was 41.1%. Predominantly de novo variants accounted for 45 out of 68 cases (66.2%), and the most frequent disease‐causing variants were missense (74%). Younger age at onset of epilepsy, female gender and electroclinical diagnosis of Dravet syndrome were associated with a higher yield as opposed to focal epilepsies. Precision medicine was considered tenable in 25/68 (36.8%) cases. Our study reveals a significant yield of trio‐WES for de novo variants in childhood‐onset DRE/DEE. Female gender, early age at onset, and specific electro‐clinical phenotypes have a higher likelihood of identifying a monogenic etiology.
Genetics in medicine : official journal of the American College of Medical Genetics · 2019
Hane Lee、Alden Y Huang、Lee-Kai Wang 等
PURPOSE: We investigated the value of transcriptome sequencing (RNAseq) in ascertaining the consequence of DNA variants on RNA transcripts to improve the diagnostic rate from exome or genome sequencing for undiagnosed Mendelian diseases spanning a wide spectrum of clinical indications. METHODS: From 234 subjects referred to the Undiagnosed Diseases Network, University of California-Los Angeles clinical site between July 2014 and August 2018, 113 were enrolled for high likelihood of having rare undiagnosed, suspected genetic conditions despite thorough prior clinical evaluation. Exome or genome sequencing and RNAseq were performed, and RNAseq data was integrated with genome sequencing data for DNA variant interpretation genome-wide. RESULTS: The molecular diagnostic rate by exome or genome sequencing was 31%. Integration of RNAseq with genome sequencing resulted in an additional seven cases with clear diagnosis of a known genetic disease. Thus, the overall molecular diagnostic rate was 38%, and 18% of all genetic diagnoses returned required RNAseq to determine variant causality. CONCLUSION: In this rare disease cohort with a wide spectrum of undiagnosed, suspected genetic conditions, RNAseq analysis increased the molecular diagnostic rate above that possible with genome sequencing analysis alone even without availability of the most appropriate tissue type to assess.
Kidney Research and Clinical Practice · 2025
Dongseok Moon、Go Hun Seo
Exome sequencing (ES) and genome sequencing (GS) are essential for diagnosing rare genetic disorders, yet a significant number of patients remain without a definitive diagnosis after the initial analysis. Reanalysis of existing ES and GS data has emerged as a clinically indispensable practice, offering the potential to solve previously unresolved cases by leveraging rapid advances in genomic knowledge and technology. This review comprehensively addresses the growing importance, clinical utility, methodologies, and challenges of ES and GS data reanalysis. The increase in diagnostic yield from reanalysis is driven by several key factors: the continuous discovery of new gene-disease associations, ongoing updates to clinical and population genetic databases like ClinVar and gnomAD, the refinement of bioinformatic pipelines, and the application of advanced analytical techniques. Reanalysis has been shown to provide an additional diagnostic yield ranging from 3% to 15% across various disease cohorts, including neurodevelopmental, renal, and cardiovascular disorders. A significant portion of these new diagnoses stems from the reclassification of variants of uncertain significance, which often leads to direct and meaningful changes in clinical management, including targeted surveillance and tailored therapies. The reanalysis of ES and GS data is no longer a supplementary activity but a fundamental component of modern genomic medicine, transforming genomic testing from a one-time event into a continuous diagnostic process. To fully realize its potential, the development of standardized guidelines is crucial to address financial, logistical, and ethical barriers and to facilitate the equitable integration of reanalysis into routine clinical care.
Genetics in Medicine · 2023
C. Chung、S. P. Y. Hue、N. Ng 等
PURPOSE
This meta-analysis aims to compare the diagnostic and clinical utility of whole-exome sequencing (WES) versus whole-genome sequencing (WGS) in pediatric and adult patients with rare diseases across diverse populations.
METHODS
A meta-analysis was conducted to identify studies from 2011-2021.
RESULTS
One-hundred-and-sixty-one studies across 31 countries/regions were eligible, featuring 50,417 probands of diverse populations. Diagnostic rates of WES (0.38, 95% CI 0.36-0.40) and WGS (0.34, 95% CI 0.30-0.38) were similar (p=0.1). Within-cohort comparison illustrated a 1.2 times odds of diagnosis by WGS over WES (95% CI 0.79-1.83, p=0.38). WGS studies discovered a higher range of novel genes than WES studies, yet the rate of variant of unknown significance (VUS) did not differ (p=0.78). Among high-quality studies, clinical utility of WGS (0.77, 95% CI 0.64-0.90) was higher than WES (0.44, 95% CI 0.30-0.58) (p<0.01).
CONCLUSION
This meta-analysis provides an important update to demonstrate the similar diagnostic rates between WES and WGS and the higher clinical utility of WGS over WES. With the newly published recommendations for clinical interpretation of variants found in non-coding regions of the genome and the trend of decreasing VUS and WGS cost, it is expected that WGS will be more widely used in clinical settings.
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AI 辅助短评，基于标题和摘要整理本文为叙述性综述，系统梳理外显子组测序阴性后重分析、变异重分类与动态报告的策略，并讨论机制导向的升级检测。选题切合临床痛点，强调将ES从一次性检测转变为纵向诊断过程。但作为综述，未提供原始验证数据，重分析与动态报告的实际增益、可操作性及成本效益仍需前瞻性研究确认。